Systems and Methods for Superdisintegrant-Based Composite Particles for Dispersion and Dissolution of Agents

ABSTRACT

The present disclosure provides improved systems and methods utilizing colloidal/ultrafine superdisintegrant-based composite particles for dispersion and/or dissolution of active pharmaceutical agents. In general, the present disclosure utilizes a surfactant-free or near surfactant-free formulation by incorporating a wet milled SDI as a dispersant in the formulation. As such, the present disclosure provides for the preparation of surfactant-free or substantially surfactant-free formulations (e.g., nano-composite micro-particle formulations) by incorporating a wet-milled superdisintegrant (SDI) as the dispersant in the formulations. The advantageous SDI particles (e.g., colloidal/ultrafine SDI particles) of the present disclosure can be used to break-up the aggregates (e.g., nanoparticle aggregates) of the active agents (e.g. poorly water-soluble drugs) in the formulations (e.g., micro-particle formulations) and enhance the recovery of the nanoparticles of active agents during aqueous re-dispersion and their dissolution rate in vitro and in vivo.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/625,082 filed Apr. 16, 2012, the contents of which is hereinincorporated by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

The research leading to the present disclosure was supported in part byfederal grants, including the NSF Grant #EEC-0540855. Accordingly, theUnited States Government may have certain rights in the disclosure.

FIELD OF THE DISCLOSURE

The present disclosure relates to superdisintegrants and, moreparticularly, to improved systems and methods utilizingsuperdisintegrant-based composite particles for dispersion and/ordissolution of active pharmaceutical agents.

BACKGROUND OF THE DISCLOSURE

In general, nanoparticles and/or sub-micron (colloidal) particles in thesize range of about 10 to about 1000 nm have found use in severalapplications due to their large surface area among other enhancedengineering properties. These particles are usually produced by wettop-down (size reduction) approaches, or bottom-up (precipitation-based)approaches. Preserving the large surface area and primary size of activenano-particulate agents such as drug substances during wet-phaseproduction and integration into nano-composite micro-particles isgenerally important.

One issue during the integration step of drying active-loadednanoparticle suspensions is that nanoparticles typically aggregateand/or agglomerate. This can lead to poor recovery of active (drug)nanoparticles when composite drug-laden micro-particles in various soliddosage forms are re-dispersed in fluids, which in turn can cause loss ofsurface area and deteriorated active functionality. Incomplete recoveryof drug nanoparticles may lead to slow drug dissolution from soliddosage forms and poor drug bioavailability, especially for poorlywater-soluble drugs.

In general, the presence of surfactants in formulations has sometimesbeen found to be important to the recovery of nanoparticles and/or theirdissolution. However, in certain applications (e.g., inhalation),surfactants generally cannot be used as they can cause irritation (e.g.,to the sensory pulmonary epithelium). In addition, the use of largeamounts of surfactants can cause physical instability of drugsuspensions through Ostwald ripening and/or agglomeration. Therefore,the development of surfactant-free formulations or formulations with aminimal amount of surfactants is highly desirable.

Dispersants such as sugars (e.g., sucrose, lactose), sugar alcohols(e.g., mannitol, sorbitol), and/or water-soluble polymers (e.g.,cellulosic polymer such as HPMC, HPC, PVP, polyvinylalcohol, longchained PEG, etc.) have been added to formulations to enhance drugnanoparticle recovery from the dried nano-composite particles in soliddosage forms. In general, they sometimes allow faster re-dispersion ofnanoparticles via enhanced wetting and/or faster matrix dissolution(e.g., wetting/dissolution mechanisms).

In general, particle size engineering is a convenient tool which may beused to control the bioavailability of drugs. Specifically, convertingbigger particles into nanoparticles significantly enhances diffusionproperties as a result of the large surface area which nanoparticlesprovide. This knowledge has been used to reduce the particle size ofpoorly water soluble drugs, via wet stirred media milling (e.g., in suchsolid dosage forms known as Rapamune©, Emend©, and Tricor©). However,incorporation of nanoparticles into solid dosage forms leads to the lossof their large surface area during drying of nano-suspensions throughsize growth and/or agglomeration (e.g., forming micro-particles greaterthan about 1 μm).

The nano-suspensions containing active agents can be dried (e.g., byspray drying, spray freeze drying, freeze drying, etc.), and granulatedwith or coated on inert excipient particles to convert them into soliddosage forms. During the drying processes, nanoparticles tend toaggregate and form larger particles (sometimes as large as about 1-10 μmparticles).

Consequently, the advantages due to the increased surface area via theproduction of nanoparticles may be lost. These nanoparticle aggregatescould be reversible or irreversible depending on the formulation and/orprocess conditions used during the drying process (see, e.g., Bhakay etal., Recovery of BCS Class II drugs during aqueous redispersion ofcore-shell type nanocomposite particles produced via fluidized bedcoating, Powder Technol., 236, 221-234 (2013)). Moreover, thenanoparticles may not be recovered or released from the solid dosageforms fast and/or completely during the re-dispersion/dissolution,either in vivo or in vitro (see, e.g., Kesisoglou et al.,Nanosizing-Oral formulation development and biopharmaceuticalevaluation, Adv. Drug Deliv. Rev. 59, 631-644 (2007)).

In some early works, drug nanoparticles were produced by wet mediamilling in the presence of hydroxypropyl cellulose (HPC) as astabilizer, followed by spray and vacuum drying, respectively (see,e.g., Lee J, Drug nano-and microparticles processed into solid dosageforms: physical properties, J. Pharm. Sci. 92, 2057-2068 (2003); Choi etal., Effect of polymer molecular weight on nanocomminution of poorlysoluble drug, Drug Delivery. 15, 347-353 (2008)). The matrix-typenano-composite micro-particles were re-dispersed in water to check thenanoparticle recovery after drying. During the re-dispersion,nano-composite micro-particles released drug nanoparticles over a periodof about 25 hours, and nanoparticle recovery was incomplete in some ofthis work. Also in this work, the micro-particles formed after vacuumdrying could not re-disperse into nanoparticles when dispersed in water,even after stirring followed by sonication.

However, drug nanoparticles have been recovered from nano-compositemicro-particles obtained from freeze/convective/vacuum drying containingdispersants (e.g., carageenum, gelatin, and alginic acid), as well asHPC as the stabilizer in the re-dispersion tests using sonication (Kimet al., Effective polymeric dispersants for vacuum, convection andfreeze drying of drug nanosuspensions, Int. J. Pharm. 397, 218-224(2010)).

Nano-suspension samples have been prepared containing the surfactantD-a-tocopherol polyethylene glycol 1000 succinate (TPGS) as thestabilizer by media milling and spray drying them to form nano-compositemicro-particles. (Van Eerdenbrugh et al., Drying of crystalline drugnanosuspensions—The importance of surface hydrophobicity on dissolutionbehavior upon redispersion, Eur. J. Pharm. Sci. 35, 127-135 (2008); VanEerdenbrugh et al., Alternative matrix formers for nanosuspensionsolidification: Dissolution performance and X-ray microanalysis as anevaluation tool for powder dispersion, Eur. J. Pharm. Sci. 35, 344-353(2008)). The drug nanoparticles of these poorly water soluble drugs inthis case were not recovered in the dissolution testing.

However, they were recovered when additional dispersants like Avicel®,Aerosil®, Fujicalin® and Inutec® were present in the formulation. Sometypical dispersants that are added to formulations to preserve thenanoparticle recovery from the dried nano-composite particles are sugars(e.g. sucrose, lactose), sugar alcohols (e.g. mannitol, sorbitol) andwater-soluble polymers (e.g. PVP, polyvinylalcohol, long chained PEG).

The ability to recover the drug nanoparticles from nano-compositeparticles containing polymer hydroxypropylmethyl cellulose (HPMC) andsurfactant sodium dodecyl sulfate (SDS) coated on lactose followed byre-dispersion in water has been shown (see, e.g., Basa et al.,Production and in vitro characterization of solid dosage formincorporating drug nanoparticles, Drug Dev. Ind. Pharm. 34, 1209-1218(2008)).

Similarly, griseofulvin (GE) nanoparticles have been recovered from thecore-shell type nano-composite micro-particles containing both HPC andSDS, or SDS alone in the nano-suspension formulation (see, e.g., Bhakayet al., Recovery of BCS Class II drugs during aqueous redispersion ofcore-shell type nanocomposite particles produced via fluidized bedcoating, Powder Technol., 236, 221-234 (2013)). However, GFnanoparticles could not be recovered in the absence of SDS, even thoughmannitol was added as the dispersant.

It has been observed that it can be difficult to reconstitute surfactantfree nanoparticles (Jeong et al., Effect of cryoprotectants on thereconstitution of surfactant-free nanoparticles ofpoly(DL-lactide-co-glycolide), J. Microencapsulation. 22, 593-601(2005)). From the above examples, surfactants in general have sometimesbeen able to re-disperse drug nanoparticles after drying.

As noted, surfactants should be either used sparingly due to theirpotential negative impact on the physical stability of thenano-suspensions, or attempted to be substantially eliminated completelydue to their toxicity especially in inhalation applications (Lebhardt etal., Surfactant-free redispersible nanoparticles in fast-dissolvingcomposite microcarriers for dry-powder inhalation, Eur. J. Pharm.Biopharm. 78, 90-96 (2011); Liversidge et al., Particle size reductionfor improvement of oral bioavailability of hydrophobic drugs: I.Absolute oral bioavailability of nanocrystalline danazol in beagle dogs,Int. J. Pharm. 125, 91-97 (1995); Liversidge et al., Surface modifieddrug nanoparticles, U.S. Pat. No. 5,145,684). Therefore, there is a needto develop surfactant-free formulations, or formulations with minimalamount of surfactants.

Superdisintegrants (“SDIs”) have been used in the past to improve thewettability of drugs by co-grinding in planetary mills and/or ball mills(see, e.g., Voinovich et al., Solid state mechanochemical simultaneousactivation of the constituents of the silybum marianum phytocomplex withcrosslinked polymers, J. Pharm. Sci. 98, 215-228 (2009); Passerini etal., A new approach to enhance oral bioavailability of silybum marianumdry extract: Association of mechanochemical activation and spraycongealing, Phytomedicine. 19, 160-168 (2012); Martini et al.,Physico-chemical characteristics of steroid-crosslinkedpolyvinylpyrrolidone coground systems, Int. J. Pharm. 75, 141-146(1991); Jalali et al., Co-grinding as an approach to enhance dissolutionrate of a poorly water-soluble drug (gliclazide), Powder Technol. 197,150-158 (2010)).

They also have been used to make solid dispersions by dispersing the SDIin a drug solution, followed by evaporation of the solvents vialyophilization, vacuum drying, or drying at room temperature (see, e.g.,Srinarong et al., Strongly enhanced dissolution rate of fenofibratesolid dispersion tablets by incorporation of superdisintegrants, Eur. J.Pharm. Biopharm. 73, 154-161 (2009; Carli et al., Influence of polymercharacteristics on drug loading into crospovidone, Int. J. Pharm. 33,115-124 (1986); Williams et al., Disorder and dissolution enhancement:Deposition of ibuprofen on to insoluble polymers, Eur. J. Pharm. Sci.26, 288-294 (2005); Nokhodchi et al., Preparation of spherical crystalagglomerates of naproxen containing disintegrant for direct tabletmaking by spherical crystallization technique, AAPS PharmSciTech. 9,54-59 (2008); Rao et al., Dissolution improvement of simvastatin bysurface solid dispersion technology, Dissolution Technol. 6, 27-34(2010)).

Solid dispersions have been prepared by mixing the drug and SDI in atheta composer, and heating to avoid the use of solvents (see, e.g.,Fujii et al., Preparation, characterization, and tableting of a soliddispersion of indomethacin with crospovidone, Int. J. Pharm. 293,145-153 (2005)). Another way of making solid dispersions is to melt thedrug and deposit it on a pre-warmed SDI as carrier (Williams et al.,2005). Commercially available SDIs have particles typically in the sizeranges of about 5 to about 100 microns.

SDIs are also commonly incorporated in tablets extra-granularly orintra-granularly (or both) for dissolution improvement. The typicalmechanisms are that the SDIs absorb water by their swelling and/orwicking actions, which breaks the tablet matrix leading to adisintegration and release of the drug from tablets (Solis et al.,Effect of disintegrants with different hygroscopicity on dissolution ofNorfloxacin/Pharmatose DCL 11 tablets, Int. J. Pharm. 216, 127-135(2001); Zhao et al., The influence of swelling capacity ofsuperdisintegrants in different pH media on the dissolution ofhydrochlorothiazide from directly compressed tablets, AAPSPharmSciTech.6, E120-E126 (2005); Balasumbramanium et al., The influence ofsuperdisintegrant choice on the rate of drug dissolution, Pharm. Tech.,44-49 (2009)).

Thus, an interest exists for improved systems and methods utilizingsuperdisintegrant-based composite particles for dispersion and/ordissolution of active pharmaceutical agents. These and otherinefficiencies and opportunities for improvement are addressed and/orovercome by the assemblies, systems and methods of the presentdisclosure.

SUMMARY OF THE DISCLOSURE

The present disclosure provides advantageous systems and methodsutilizing superdisintegrant-based composite particles for dispersionand/or dissolution of active pharmaceutical agents. In exemplaryembodiments, the present disclosure utilizes a surfactant-free or nearsurfactant-free formulation by incorporating a wet milledsuperdisintegrant (SDI) as a dispersant in the formulation. Statedanother way, the present disclosure provides for the preparation ofsurfactant-free or near surfactant-free formulations (e.g.,nano-composite micro-particle formulations) by incorporating awet-milled superdisintegrant (SDI) as the dispersant in the formulation.

Moreover, the advantageous SDI particles (e.g., colloidal/ultrafine SDIparticles) of the present disclosure can also be used to break-up theaggregates (e.g., nanoparticle aggregates) of the active agents (e.g.poorly water-soluble drugs) in the formulations (e.g., micro-particleformulations). The aggregates are typically produced by drying of thedrug—SDI suspensions (e.g., nano-suspensions).

In certain embodiments, the present disclosure provides for theproduction of SDI particles/formulations (e.g., nano/colloidal/ultrafineSDI particles/formulations) by wet milling and/or wet co-grinding theactive agents (e.g., poorly water-soluble drugs) along with the SDIs ina wet-stirred media mill in the absence of surfactants or with minimalsurfactants present.

The subsequent drying of these suspensions embeds the wet-milled SDIparticles along with the active agent (drug). For example, thewet-milled SDI particles along with the active agent may be embedded inthe shell of a core-shell (e.g., layered) type formulation (e.g.,nano-composite micro-particles formulation), which can be produced bycoating on excipients in a fluidized bed dryer/coater or the like. Thewet-milled SDI particles along with the active agent may also beembedded in the matrix/formulation of particles (e.g., nano-compositeparticles) produced by suitable drying techniques (e.g., spray drying,vacuum drying, freeze drying, spray freeze drying oven drying, etc.).

The improved systems and methods of the present disclosureadvantageously use SDIs (e.g., colloidal/ultrafine SDIs) as dispersantsin formulations (e.g., nano-composite micro-particle formulations),and/or in solid dosage forms/formulations (e.g., formulations containingsuch composite micro-particles) to achieve fast recovery of activeagents (e.g., drug nanoparticles) from solid dosage forms and/or ensuingfast active agent (drug) dissolution.

Embodiments of the present disclosure utilize wet-milled SDIs and/or wetco-ground SDIs along with active agents to form particles/formulations(e.g., nanoparticles or ultrafine particles/formulations) in thepresence of stabilizers (e.g., polymeric stabilizers). Thesuspensions/formulations (e.g., nanoparticle suspensions,nano-suspensions) containing SDI and active agents (e.g., drugs) can bedried for their incorporation in solid dosage forms (e.g., tablets,capsules, strip films, sachets, dry powder inhalers, etc.). In certainembodiments of the present disclosure, SDI particles can also be milledalone into particles (e.g., colloidal/ultrafine particles ornanoparticles) without the active agents in a wet stirred media mill orthe like.

The advantageous applications of the SDIs with active agents enablegreater recovery of active agent particles (e.g., active agent particlesnanoparticles). The present disclosure allows for the quicker/faster andmore effective recovery and/or dissolution of active agents (drugs, suchas poorly water-soluble drug nanoparticles) from formulations (e.g.,nano-composite micro-particles/formulations) via the production of SDIparticles (e.g., nano, ultrafine, sub-micron and/or colloidal SDIinsoluble dispersant particles), and their incorporation into suchformulations (e.g., nano-composite micro-particle formulations).

The present disclosure provides for both SDI particles that are milledalone, or co-ground/co-milled along with active agents (e.g., poorlywater-soluble drugs), in a wet-stirred media mill in the presence ofstabilizers (e.g., polymeric stabilizers) without the addition ofsurfactants (or with minimal amount of surfactants) to prepareformulations (e.g., nanoparticle suspensions/formulations) of the SDIsand/or active agents.

A suspension/formulation of co-ground SDI particles with active agentsand polymeric stabilizers can be dried by a suitable drying method forthe preparation of drug formulations (e.g., nano-compositemicro-particle drug formulations). Then, these formulations can be usedas powders (e.g., in sachets), or can be incorporated into capsules ortablets, preferably after the addition of generally regarded as safe(GRAS) pharmaceutical excipients (e.g., celluloses, starch, lactose,etc.). The drying methods may include, without limitation, fluidized bedcoating/drying/granulation, spray-drying, freeze-drying, vacuum/ovendrying, etc.

As such, the systems/methods of the present disclosure lead to theproduction of surfactant-free (or with minimal surfactants) formulations(e.g., nano-composite micro-particle formulations), which can then beincorporated into a standard solid dosage form or the like via standardpharmaceutical operations (e.g., blending, capsule filling, tableting,etc.).

One advantageous aspect of the present disclosure is the production ofcolloidal (e.g., typically about 50 to about 500 nm) and/or ultrafine(e.g., typically about 50 to about 5000 nm) superdisintegrant particlesby wet milling, either alone or along with active agents (e.g., poorlywater-soluble drugs), for the subsequent production/fabrication offast/quickly-dispersing and/or dissolving formulations (e.g.,nano-composite micro-particle formulations).

It has advantageously been demonstrated that the active agents (e.g.,drugs, such as poorly water-soluble drug nanoparticles) are recoveredquickly and/or more effectively from the formulations (e.g.,nano-composite micro-particle formulations containing the wet-milledSDIs) during aqueous re-dispersion under relatively low mechanicalagitation/sonication, and significant drug dissolution rate improvementshave been achieved in standard dissolution tests. These particles ormicro-particles may be incorporated in a standard solid dosage form asmentioned above. It is also noted that the feasibility of wet mediamilling of the SDI particles alone into particles/nanoparticles or thelike has been confirmed by the present disclosure.

The present disclosure provides for a method for fabricating aformulation including providing superdisintegrant (SDI) particles;providing active agent particles; co-wet-milling the SDI particles andthe active agent particles to form a mixture of wet-milled SDI particlesand active agent particles.

The present disclosure also provides for a method for fabricating aformulation further including the step of drying the mixture ofwet-milled SDI particles and active agent particles. The presentdisclosure also provides for a method for fabricating a formulationfurther including the step of incorporating the dried mixture into asolid dosage form. The present disclosure also provides for a method forfabricating a formulation wherein at least a portion of the driedmixture is coated on an excipient.

The present disclosure also provides for a method for fabricating aformulation wherein the drying step includes a drying technique selectedfrom the group consisting of fluidized bed drying, spray drying, vacuumdrying, freeze drying, spray freeze drying, oven drying, fluidized bedcoating and fluidized bed granulation. The present disclosure alsoprovides for a method for fabricating a formulation wherein the mixturefurther includes a stabilizer. The present disclosure also provides fora method for fabricating a formulation wherein the stabilizer isselected from the group consisting of soluble polymers,hydroxpropylmethyl cellulose, hydroxpropyl cellulose andpolyvinylpyrrolidone and combinations thereof.

The present disclosure also provides for a method for fabricating aformulation wherein the mixture of wet-milled SDI particles and activeagent particles is a suspension of SDI particles and active agentparticles. The present disclosure also provides for a method forfabricating a formulation wherein the suspension contains colloidal andultrafine SDI particles, and colloidal particles and nanoparticles ofactive agents. The present disclosure also provides for a method forfabricating a formulation further including the step of drying thesuspension to form a nano-composite of SDI and active agentmicro-particles.

The present disclosure also provides for a method for fabricating aformulation wherein the active agent particles include particlesselected from the group consisting of pharmaceutical active agents,poorly water soluble drugs, diagnostic agents, peptides, proteins,biologic agents and combinations thereof. The present disclosure alsoprovides for a method for fabricating a formulation wherein the SDIparticles and active agent particles are co-wet-milled in a wet mediamill with milling media; and wherein the milling media has a particlesize of about 25 μm to about 4 mm.

The present disclosure also provides for a method for fabricating aformulation wherein the SDI particles and active agent particles areco-wet-milled in size reduction equipment selected from the groupconsisting of wet stirred media mill, wet ball mill, planetary mill, andmilling equipment utilizing a high pressure homogenizer. The presentdisclosure also provides for a method for fabricating a formulationwherein the SDI particles include particles selected from the groupconsisting of croscarmellose sodium particles, sodium starch glycolateparticles, crosslinked polyvinyl pyrrolidone particles, anionic SDIparticles and neutral SDI particles.

The present disclosure also provides for a method for fabricating aformulation wherein the wet-milled SDI particles have a particle size ofless than about 5 microns. The present disclosure also provides for amethod for fabricating a formulation wherein the mixture of wet-milledSDI particles and active agent particles is a suspension of SDIparticles and active agent particles; and further including the step ofcoating and drying the suspension onto an excipient via a fluidized bedprocessor to form a nano-composite of SDI and active agent particles onat least a portion of the excipient.

The present disclosure also provides for a method for fabricating aformulation wherein prior to wet-milling the SDI particles and activeagent particles, the SDI particles are provided in a suspension at aweight/weight (w/w) % of from about 0.50 w/w % to about 5.0 w/w % withrespect to the weight of the water or suspension; and wherein the activeagent particles are provided in the suspension at a weight/weight (w/w)% of from about 5.0 w/w to about 40.0 w/w % with respect to the weightof the water or suspension.

The present disclosure also provides for a method for fabricating aformulation wherein the mixture of wet-milled SDI particles and activeagent particles is a suspension of SDI particles and active agentparticles; and further including the step of drying the suspension via aspray dryer to form a nano-composite of SDI and active agent particles.

The present disclosure also provides for a method for fabricatingcolloidal and ultrafine superdisintegrant (SDI) particles includingproviding SDI particles; wet-milling the SDI particles in a wet mediamill to form colloidal and ultrafine SDI particles; wherein thewet-milled SDI particles have a particle size of less than about 5microns.

The present disclosure also provides for a method for fabricatingcolloidal and ultrafine SDI particles wherein the wet-milled SDImicro-particles have a particle size of about 50 nm to about 1000 nm.The present disclosure also provides for a method for fabricatingcolloidal and ultrafine SDI particles further including the step ofadding the wet-milled SDI micro-particles to active agent particles. Thepresent disclosure also provides for a method for fabricating colloidaland ultrafine SDI particles wherein the wet-milled SDI micro-particlesare mixed with the active agent particles to form a suspension. Thepresent disclosure also provides for a method for fabricating colloidaland ultrafine SDI particles wherein at least a portion of the activeagent particles are in powder form.

The present disclosure also provides for a method for fabricatingcolloidal and ultrafine SDI particles wherein prior to wet-milling theSDI particles, the SDI particles are provided in a suspension at aweight/weight (w/w) % of from about 0.50 w/w % to about 5.0 w/w % withrespect to the weight of the water or suspension.

The present disclosure also provides for a method for fabricatingcolloidal and ultrafine SDI particles further including the steps of:(i) drying the suspension to form a composite of SDI and active agentparticles, and (ii) incorporating the dried composite into a soliddosage form.

The present disclosure also provides for a method for fabricatingcolloidal and ultrafine SDI particles wherein the wet media millincludes milling media, the milling media having a particle size ofabout 25 μm to about 4 mm. The present disclosure also provides for amethod for fabricating colloidal and ultrafine SDI particles furtherincluding the step of coating and drying the suspension onto anexcipient via a fluidized bed processor to form a composite of SDI andactive agent particles on at least a portion of the excipient.

The present disclosure also provides for a method for fabricating aformulation including providing superdisintegrant (SDI) particles andactive agent particles in a suspension, the SDI particles provided inthe suspension at a weight/weight (w/w) % of from about 0.50 w/w % toabout 5.0 w/w % with respect to the weight of the water or suspension;co-wet-milling the SDI particles and the active agent particles in a wetmedia mill to form a nano-particle suspension of wet-milled SDIparticles and active agent particles; drying the nano-particlesuspension to form a nano-composite of SDI and active agentmicro-particles; incorporating the dried nano-composite into a soliddosage form; wherein the wet-milled SDI particles have a particle sizeof less than about 5 microns.

Any combination or permutation of embodiments is envisioned. Additionaladvantageous features, functions and applications of the disclosedassemblies, systems and methods of the present disclosure will beapparent from the description which follows, particularly when read inconjunction with the appended figures. All references listed in thisdisclosure are hereby incorporated by reference in their entireties.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the present disclosure are further describedwith reference to the appended figures. It is to be noted that thevarious steps, features and combinations of steps/features describedbelow and illustrated in the figures can be arranged and organizeddifferently to result in embodiments which are still within the spiritand scope of the present disclosure. To assist those of ordinary skillin the art in making and using the disclosed systems, assemblies andmethods, reference is made to the appended figures, wherein:

FIG. 1 illustrates the evolution of the cumulative particle sizedistribution of SSG particles during wet media milling withoutstabilizers in water;

FIG. 2 depicts the SEM image of SSG particles milled for about 4 hourswithout stabilizers in water;

FIG. 3 shows the cumulative particle size distribution of FNB and CCSduring co-grinding of FNB (about 10% w/w) and CCS (about 1% w/w) withHPMC E3 (about 1% w/w) as the stabilizer without surfactant in wet mediamill;

FIG. 4 illustrates the SEM image of co-ground FNB and CCS after millingin the wet media mill for about 2.75 hours in the presence of HPMC E3without surfactant;

FIG. 5 depicts cumulative particle size distribution of GF and CCS afterco-grinding of GF (about 10% w/w) and CCS (about 0.9% w/w) with HPC(about 2.5% w/w) as the stabilizer without surfactant in wet media mill;

FIG. 6 shows the particle size distribution of milled suspensions beforecoating and after re-dispersion in water;

FIG. 7 demonstrates the dissolution profile of GF from nano-compositemicro-particles produced with different suspension formulations: about2.5% HPC, about 2.5% HPC with Mannitol, about 2.5% HPC with CCS, andabout 2.5% HPC with SDS;

FIG. 8 illustrates the evolution of the cumulative particle sizedistribution of CP particles during wet media milling withoutstabilizers in water;

FIG. 9 depicts the SEM image of CP particles milled for about 4 hourswithout stabilizers in water;

FIG. 10 shows the cumulative particle size distribution of FNB and SSGduring co-grinding of FNB (about 10% w/w) and SSG (about 3% w/w) withHPMC-E3 (about 1% w/w) as the stabilizer without surfactant in wet mediamill;

FIG. 11 illustrates the SEM image of co-ground FNB and SSG after millingfor about 2.75 hours in the presence of HPMC E3 without surfactant;

FIGS. 12A-C depict EDX analysis of co-ground FNB and SSG milled samplefor detecting sodium (from SSG) and chlorine (from FNB);

FIG. 13 is a SEM image of GF suspension milled in the absence ofstabilizers (Run 1);

FIG. 14 shows wet stirred media milling of about 10% GF and about 0.9%CCS in the presence of about 2.5% HPC (Run 7) as an evolution of thecumulative particle size distribution over a period of about 240minutes;

FIG. 15 is a SEM image of the suspension in FIG. 14 after about 240minutes milling;

FIGS. 16A-D display SEM images of: (A) uncoated Pharmatose® particles,(B) Pharmatose® particles after coating with about 10% GF/about 2.5%HPC/about 0.5% SDS suspension (Run 4 NCMPs), (C) the surface of a Run 4NCMP showing embedded GF nanoparticles, and (D) the cross-section of aRun 4 NCMP;

FIGS. 17A-D display video images captured during the re-dispersion ofvarious NCMPs, with different dispersants, in quiescent deionized water:a) 30 min after re-dispersion and evolution of the re-dispersion in thefirst 300 s for NCMPs with b) 2.5% HPC, c) 2.5% HPC/0.5% SDS, and d)2.5% HPC/0.9% CCS (M 60 min) in the precursor suspensions. M: milled;

FIGS. 18A-F display SEM images of GF NCMPs after 2 min re-dispersion inwater by paddle stirring followed by overnight drying in vacuum—NCMPscontaining: (A) GF milled in the absence of stabilizers (Run 1), (B) GFmilled with 2.5% HPC (Run 2), (C) GF milled with 2.5% HPC followed byaddition of Mannitol (Run 3), (D) GF milled with 2.5% HPC and 0.5% SDS(Run 4), (E) GF milled with 2.5% HPC followed by addition of 0.9%un-milled CCS (Run 5), and (F) GF milled with 2.5% HPC and 0.9% CCS for60 min (Run 6);

FIG. 19 displays an evolution of GF released and dissolved from theNCMPs during the USP II dissolution test; the NCMPs were prepared usingvarious milled suspensions (Runs 1-8) and from a physical mixture of theun-milled CCS particles with Run 2 NCMPs (about 2.5% HPC/about 10% GF);CCS was present outside the NCMPs in the physical mixture;

FIG. 20 displays a correlation between percentage of GF dissolved inabout 2 min in the USP II dissolution test and percentage of GFnanoparticles recovered in about 2 min during the redispersion test; and

FIG. 21 illustrates the dissolution profile (dissolution medium-water)of GF from spray dried nano-composite micro-particles produced withdifferent suspension formulations: about 2.5% HPC, and about 2.5%HPC/about 1% SSG.

DETAILED DESCRIPTION OF DISCLOSURE

The following is a detailed description of the disclosure provided toaid those skilled in the art in practicing the present disclosure. Thoseof ordinary skill in the art may make modifications and variations inthe embodiments described herein without departing from the spirit orscope of the present disclosure. Unless otherwise defined, the technicaland scientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art. The terminology used inthe description of the disclosure herein is for describing particularembodiments only, and is not intended to be limiting of the disclosure.All publications, patent applications, patents, figures and otherreferences mentioned herein are expressly incorporated by reference intheir entireties.

The present disclosure provides improved systems and methods utilizingsuperdisintegrant-based composite particles for dispersion and/ordissolution of active pharmaceutical agents. In exemplary embodiments,the present disclosure utilizes a surfactant-free or nearsurfactant-free formulation by incorporating a wet milled SDI as adispersant in the formulation. Stated another way, the preparation ofsurfactant-free or substantially surfactant-free formulations (e.g.,nano-composite micro-particle formulations) by incorporating awet-milled superdisintegrant (SDI) as the dispersant in the formulationsis provided.

The advantageous SDI particles (e.g., colloidal/ultrafine SDI particles)of the present disclosure can also be used to break-up the aggregates(e.g., nanoparticle aggregates) of the active agents (e.g. poorlywater-soluble drugs) in the formulations (e.g., micro-particleformulations).

Current practice provides that commercially available SDI particles aretypically in the size ranges of about 5 to about 100 microns, and thatcolloidal and/or ultrafine SDI particles have not been produced in theart by wet milling. In exemplary embodiments, the present disclosureprovides for the co-grinding of SDIs with active agents in the absenceof surfactants (or with minimal surfactants), and using theSDIs/composite on the nano/ultrafine/sub-micron/colloidal scale withoutsurfactants (or with minimal surfactants), thereby providing asignificant manufacturing, commercial and/or environmental advantage asa result. Moreover, the systems/methods of the present disclosureadvantageously lead to the improved or substantially complete recoveryof the active agents without (or with minimal) surfactants. According toexemplary systems/methods of the present disclosure, it is noted thatcolloidal and/or ultrafine SDI particles can now be produced by wetmilling.

In certain embodiments, the present disclosure provides for theproduction of nano/colloidal/ultrafine SDI particles by wet milling, andwet co-grinding of the active agents (e.g., poorly water-soluble drugs)along with the SDIs in a wet stirred media mill in the absence ofsurfactants or with minimal surfactants present.

As noted, the subsequent drying of these suspensions can embed thewet-milled SDI particles along with the active agent (drug). In certainembodiments, the wet-milled SDI particles along with the active agentmay be embedded in the shell of a core-shell (e.g., layered) typeformulation (e.g., nano-composite micro-particles formulation), whichcan be produced by coating on excipients in a fluidized bed dryer/coateror the like. In other embodiments, the wet-milled SDI particles alongwith the active agent may be embedded in the matrix/formulation ofparticles (e.g., nano-composite particles) produced by suitable dryingtechniques (e.g., spray drying, vacuum drying, freeze drying, sprayfreeze drying, oven drying, etc.).

The systems and methods of the present disclosure advantageously produceSDIs particles (e.g., colloidal/ultrafine SDIs particles) by wet millingand/or co-grinding the SDIs with active agents in a wet stirred mediamill or in a wet mill, in general. As such, the systems/methods of thepresent disclosure can use colloidal/ultrafine SDIs as dispersants innano-composite micro-particle formulations and solid dosage formscontaining such micro-particles to achieve faster/quicker recovery ofdrug nanoparticles from solid dosage forms and/or ensuringfaster/quicker drug dissolution.

Exemplary embodiments utilize wet-milled SDIs and/or wet co-ground SDIsalong with active agents to form particles/formulations (e.g.,nanoparticles or ultrafine particles/formulations) in the presence ofstabilizers (e.g., polymeric stabilizers). The suspensions/formulations(e.g., nanoparticle suspensions) containing SDI and active agents (e.g.,drugs) can be dried for their incorporation in solid dosage forms (e.g.,tablets, capsules, strip films, sachets, dry powder inhalers, etc.). Incertain embodiments, SDI particles can also be milled alone intoparticles (e.g., colloidal/ultrafine particles or nanoparticles) withoutthe active agents in a wet stirred media mill or the like.

In some embodiments, ultrafine (e.g., about 1 to about 10 microns,preferably less than about 5 microns) and/or colloidal or sub-micron(e.g., less than about 1 micron) particles of superdisintegrants (SDIs)(e.g., croscarmellose sodium, sodium starch glycolate, cross-linkedpolyvinyl pyrrolidone, etc.) are produced/fabricated via wet milling insuitable milling or size reduction equipment (e.g., wet stirred mediamilling, wet ball milling, planetary mill, milling equipment utilizinghigh pressure homogenization, etc.).

SDIs can be co-ground with pharmaceuticals agents (e.g., poorly watersoluble drugs) during wet milling in suitable size reduction equipment.The colloidal/ultrafine SDIs can be prepared via wet milling and thenmixed with suspensions or powders of pharmaceutical agents including,but not limited to, poorly water-soluble drugs (e.g., BCS Classes II andIV), diagnostic agents, peptides, proteins, biologics, etc. It has beendemonstrated that co-grinding SDIs (e.g., wet-milled anionic/neutralSDIs) with drugs (e.g., poorly water-soluble drugs) facilitates thestabilization of the co-ground suspensions.

In general, suspensions containing milled SDIs and pharmaceutical agents(e.g. drugs) can be dried using a suitable drying method known in theart. The present disclosure provides that wet-milled SDIsenable/facilitate the production of surfactant-free nano-compositeparticle formulations, which thereby allows for the release andefficient recovery and/or dissolution of drug nanoparticles from theformulations. These suspensions/formulations or compositemicro-particles can be used as powders, or can be incorporated (e.g.,after blending) with commonly used pharmaceutical excipients into astandard solid dosage form such as capsules or tablets through variousstandard pharmaceutical processes (e.g., granulation, tableting andcapsule filling, etc.).

In exemplary embodiments, nano-composite micro-particles produced fromfluidized bed coating/drying or spray-drying of co-groundsuspensions/formulations of active agents (e.g., poorly water-solubledrugs) and SDIs in a polymer solution exhibited fast release/recovery ofdrug nanoparticles during aqueous re-dispersion in water. Some drugnanoparticles were recovered within a few minutes even in quiescentwater (e.g., without agitation/stirring). Moreover, under paddlestirring, the micro-particles released a considerable fraction of thenanoparticles (16-42%) in about 2 minutes. Importantly, they alsoexhibited fast/quick drug dissolution (e.g., greater than about 80% drugdissolved within about 10 minutes).

The exemplary co-ground superdisintegrants of the present disclosure aresuperior to sugars or their alcohols or commonly used neutral polymersas dispersants, and they can replace the surfactants to a significantextent in the production of surfactant-free formulations. As such, thepresent disclosure advantageously provides forcompositions/forms/formulations (e.g., suspensions, solid dosage forms)containing SDI particles (e.g., colloidal and/or ultrafine colloidal SDIparticles) produced/fabricated by wet-milling or the like.

In general, SDIs improve tablet dissolution by changing the nature ofthe drug and/or by promoting the wettability of drugs. SDI's canaccomplish this as a result of their swelling or wicking action whichbreaks the tablet matrix or drug aggregates in the tablet, leading todisintegration of the drug.

Similarly, it is noted that the exemplary SDIs can break nanoparticleaggregates produced during the drying of nano-suspensions. Certainembodiments of the present disclosure utilize ultrafine (e.g., about1-10 microns) and/or sub-micron (e.g., less than about 1 micron) SDIparticles in certain formulations, thus eliminating/reducing the needfor other less effective dispersants such as, for example, surfactants,sugars, sugar alcohols, and/or water soluble polymers.

The present disclosure will be further described with respect to thefollowing examples; however, the scope of the disclosure is not limitedthereby. The following examples illustrate the advantageous systems andmethods of the present disclosure of utilizing SDI-based compositeparticles for dispersion and/or dissolution of active pharmaceuticalagents. As such, the present disclosure advantageously utilizes asurfactant-free or substantially surfactant-free formulation byincorporating a wet milled SDI as a dispersant in the formulation.Stated another way, the preparation of surfactant-free or substantiallysurfactant-free formulations (e.g., nano-composite micro-particleformulations) by incorporating a wet-milled superdisintegrant (SDI) asthe dispersant in the formulations is provided. As noted, the improvedSDI particles (e.g., colloidal/ultrafine SDI particles) of the presentdisclosure can also be used to break-up the aggregates (e.g.,nanoparticle aggregates) of the active agents (e.g. poorly water-solubledrugs) in the formulations (e.g., micro-particle formulations).

Example 1 Wet Media Milling of a SDI (SSG: Sodium Starch Glycolate)

An SDI, as received sodium starch glycolate (SSG) was sieved in a sieveshaker (Octagon 200) using the US Standard Testing Sieve (ASTM E-11specification). The sieves had mesh openings of about 106, 63, 45, 38and about 25 μm. The sieve shaker was operated at an amplitude of about6 for about 1 hour, and the SSG particles less than about 38 μm werecollected and used for media milling.

De-ionized water (about 196 g) was poured into the holding tank andpumped through the milling chamber at a flow rate of about 155 to about160 ml/min. The percentages weight/weight (“w/w”) are expressed withrespect to weight of the suspension/mixture. Zirconia beads of about 400μm were used as the milling media, although the present disclosure isnot limited thereto. Rather, it is noted that a variety of milling mediamay be used with the systems and methods of the present disclosure(e.g., milling media having a particle size of about 25 μm to about 4mm, such as, for example, crosslinked polystyrene beads, and othersuitable milling media or the like).

SSG (about 2% w/w) was added gradually in small amounts within about 12minutes, while the mill (Netzsch Microcer mill) was running at about3600 rpm (about 13.2 m/s tip speed). This gradual addition helpedprevent lump formation of the SSG particles and prevented clogging ofthe screen with large, swollen SDI particles. After the addition of SSG,milling was continued for about 3 minutes to ensure proper mixing. Asample was then taken from the holding tank for particle sizemeasurement and was reported as the 0 minute particle size. Thesuspension/mixture was then milled for about 4 hours.

Samples were taken at 0, 0.5, 1, 2, 3 and 4 hours to investigate thebreakage dynamics of SSG in the wet media mill (FIG. 1). The temperatureof the mill was kept below about 40° C. with the help of a chillerattached to the mill. An SEM image is shown in FIG. 2. The particle sizedistributions of the SSG suspensions were measured by laser diffractionvia Coulter LS13320 (Beckman Coulter, Miami, Fla., USA) using the Mietheory. The SEM images were taken using scanning electron microscope LEO1530 SVMP (Carl Zeiss Inc., Peabody, Mass., USA). FIGS. 1-2 present theevolution of the SSG particle size distributions during milling and anSEM image of the milled SSG particles, respectively.

The D90 (e.g., about 90% passing sizes of the cumulative volumedistribution) of the 0 minute sample of SSG is about 80 μm, even thoughits size in the dry form is about 38 μm because it swells in water. TheD90, of SSG was reduced to about 200 nm after 4 hour milling in the wetmedia mill, as can be seen from FIGS. 1-2.

The breakage occurs inside the mill due to frequent bead-bead collisionsand fragmentation of the captured particles between the colliding beads.Without being bound by any theory, it is believed that theswelling-induced softening of the SSG particles allowed fast and massivebreakage of the SDI particles. Substantially no aggregation of theparticles was observed since SSG is an anionic, cross-linked biopolymerthat prevents aggregation due to electrostatic repulsion forces. Thus,the feasibility of wet milling the SDI particles down to ultrafine,sub-micron or nano-particles (e.g., less than about 300 nm) has beenshown.

Example 2 Wet Co-Grinding of a SDI (CCS: Croscarmellose Sodium) and TwoPoorly Water-Soluble Drugs SFNB: Fenofibrate and GF: Griseofulvin) in aWet Stirred Media Mill

The co-grinding of SDI with an active agent (e.g., poorly water-solubledrug), including the mixing of the SDI croscarmellose sodium (CCS) andtwo BCS II drugs (poorly water soluble drugs) in a wet media mill.

As received CCS particles were sieved using the same conditions as thoseused for SSG in Example 1 above, and the particles less than about 38 μmwere used for the co-grinding experiments. To impart stability toco-ground suspensions/mixtures, a steric stabilizer such as a solublebiopolymer (e.g., hydroxpropylmethyl cellulose (HPMC), hydroxpropylcellulose (HPC), polyvinylpyrrolidone (PVP), etc.) can be used.

HPMC (HPMC E3 grade, about 1% w/w) was first dissolved in de-ionizedwater (about 200 g), and Fenofibrate (FNB, a model BCS Class II drug,about 10% w/w) was then added to the stabilizer solution and dispersedfor about 30 minutes with a shear mixer. Following thesuspension/mixture preparation, the entire batch was poured into theholding tank of the Netzsch mill and pumped through the mill at a speedof about 126 ml/min.

Zirconia beads with a median size of about 400 μm were used as themilling media. Milling speed was set at about 3200 rpm and CCS (about 1%w/w) was added periodically (step-wise) within about 12 minutes to theholding tank to prevent the lumping of CCS particles which may result inclogging of the mill screen (about 200 μm). After the addition of CCS,milling was continued for about 3 minutes to ensure proper mixing. Asample was then taken from the holding tank for particle sizemeasurement and was reported as the 0 minute particle size.

The suspension was then milled for about 2.75 hours at a tip speed ofabout 11.8 m/s (3200 rpm). Samples were taken at about 0, 0.5, 1, 2 andabout 2.75 hours to study the breakage dynamics during co-grinding.

FIG. 3 shows the decrease in particle size of co-grounddrug-superdisintegrant (FNB-CCS) as the milling proceeded. The mediansize (D50) was reduced to about 200 nm after milling for about 2.75hours, which was also confirmed by the SEM Image (FIG. 4). HPMC reducesthe interfacial tension between FNB and water, and acts as a stericstabilizer. CCS is a hydrophilic, anionic SDI which helps to stabilizethe suspension further due to electrostatic repulsion.

In another experiment and utilizing the same protocol and millingconditions as noted above, another BCS II drug griseofulvin (GF) atabout 10% w/w was co-ground with CCS (about 0.9% w/w) in the presence ofHPC (SL grade, about 2.5% w/w) as the stabilizer. This sample was milledfor about 80 minutes.

It is noted that the SDI particles may be provided in a suspension at aweight/weight (w/w) % of from about 0.50 w/w % to about 5.0 w/w % withrespect to the weight of the water or suspension (preferably at aweight/weight (w/w) % of from about 0.90 w/w % to about 3.0 w/w %), andthe active agent particles may be provided in the suspension at aweight/weight (w/w) % of from about 5.0 w/w % to about 40.0 w/w % withrespect to the weight of the water or suspension (preferably at aweight/weight (w/w) % of from about 10.0 w/w % to about 30.0 w/w %).

The D50 of the other co-ground drug-SDI (GF-CCS) was reduced to about180 nm (see FIG. 5) after milling for about 80 minutes with HPC as thestabilizer. The milling time of the two drugs varies because of thedifferences in the breakage strength of the two drugs, e.g., FNB and GF.

Other experiments of the present disclosure include the effectiverecovery of the active agents after co-grinding with SDIs. One exemplaryembodiment for recovering the active agent can be shown using co-groundCCS with GF in nano-composite micro-particles for recovery of GFnanoparticles after drying.

The media milling conditions described in the CCS and BCS Class II drugsexample described above were used for co-grinding about 0.9% CCS andabout 10% GF in about 2.5% HPC solution.

The results from these suspensions were compared to three otherformulations: (i) about 2.5% HPC (Hydroxpropyl cellulose, polymer), (ii)about 2.5% HPC with about 0% Mannitol (Mann, sugar alcohol), and (iii)about 2.5% HPC with about 0.5% SDS (sodium dodecyl sulfate, anionicsurfactant). The milling conditions used to prepare these suspensionswere same as those used in the previous example. All the suspensionswere milled for about 80 minutes. It is noted that other surfactants(e.g., polymeric surfactants) may be utilized, preferably in quantitiesmuch smaller than their critical micelle concentration, or none at allin surfactant-free formulations.

The suspensions prepared by wet media milling were dried, and thencoated on Pharmatose® carrier particles in a conventional bench-topfluidized bed with the top spray configuration. About 100 g Pharmatose®powder with D10, D50, and D90 values of about 58 μm, 116 μm, and 206 μmwas charged in the product bowl, and fluidized at an inlet air pressureof about 0.4-0.5 bar.

After the powder was fluidized, the heater and suspension spray wereturned on. Approximately 200 g suspension was pumped through aperistaltic pump at a constant speed of about 0.60 ml/min. Thesuspensions were mixed homogenously with a magnetic stirrer throughoutthe coating run to prevent sedimentation of particles. The suspensionswere atomized through a bi-fluid nozzle with about 0.3 mm nozzlediameter (diameter of the liquid tip) at an atomization air pressure ofabout 1 bar. The fluidization air temperature was set at about 70° C.The coated powder continued to fluidize and dry for about 10 minutesafter the suspension was sprayed. The coated powders were then testedfor particle size, and used in re-dispersion and dissolution tests.

About a gram of the nano-composite micro-particles were weighed anddispersed in about 30 ml water for about 2 minutes using sonication.Pharmatose, which forms the core of the coated particles, dissolves inwater within about 40 seconds, therefore, the particle size resultsobtained from Coulter were mainly the sizes of GF and CCS particles andtheir clusters. Sonication of the sample for about 2 minuteshelped/facilitate coated particles to establish good contact with water,and prevented sedimentation of the particles. After dispersing thecoated particles in water for about 2 minutes, an aliquot of the samplewas taken while the sample was being sonicated and the particle size wasmeasured in LS13320. Dissolution of the coated particles were thendetermined.

FIG. 6 shows the particle size distribution of the milled suspensionsbefore coating and after re-dispersion from the nano-composite particlesthat were obtained from fluidized bed coating/drying. The median size ofabout 2.5% HPC and about 2.5% HPC with about 10% Mannitol was about 1.6μm. HPC alone could not disperse the soft aggregates of GF. The mediansize of GF reduced to about 160 nm in the presence of SDS with HPC.

SDS is an anionic surfactant and reduces the interfacial tension betweenwater and the hydrophobic GF particles, which allows proper wetting ofthe particles and de-aggregation of the aggregates. Co-grinding of GFand CCS in the presence of HPC also produced nano-suspensions with amedian size of about 180 nm.

Furthermore, it can be seen that nanoparticles were recovered from thenano-composite particles for formulations containing SDS and CCS. SDSpromotes wettability of the nano-composite particles by reducing theinterfacial tension. In the absence of SDS, the dissolution action ofMannitol was not enough to disperse the GF aggregates, but it could bedispersed when an insoluble dispersant such as CCS was incorporated inthe formulation. CCS is hydrophilic in nature and absorbs water bywicking. It swells on absorption of water, and due to the swellingmechanism it breaks the shell of the nano-composite micro-particles(e.g., coated Pharmatose) and the GF aggregates.

The corresponding improvement in dissolution rate was also observed, asshown in FIG. 7. About 76% of GF was dissolved in about 2 minutes fromthe GF/HPC/CCS nano-composite particles, whereas only about 15% andabout 7% GF was dissolved from GF/HPC/Manni and GF/HPC nanocompositeparticles, respectively. CCS promotes wettability and recovers GFnanoparticles by its swelling action which leads to increaseddissolution rate. However, the highest dissolution rate was observedwhen SDS was present. These results suggest the feasibility ofsurfactant-free formulations for improving drug nanoparticlesre-dispersion and drug dissolution based on wet milledsuperdisintegrants.

In addition, the colloidal and/or ultrafine superdisintegrants preparedvia wet milling in the present disclosure allow potential minimizationof surfactants in pharmaceutical formulations. It is noted that thenano-composite micro-particles (e.g., powders) containing colloidaland/or ultrafine SDIs prepared via wet milling can be incorporated intoany standard dosage forms, and the benefits can be extended to differentdosage forms.

In certain embodiments, surfactant-free wet milled suspensions of SDIsand active agents were used as-is, while in other embodiments they weredried into composite micro-particles via standard drying operations.Drying the suspensions embeds the SDI along with the active agent in theshell of core shell type nano-composite micro-particles. These driedmicro-particles can be directly filled into solid dosage formsincluding, but not limited to, tablets, capsules, strip films, sachets,dry powder inhalers.

In further embodiments, the micro-particles are compressed into tabletsafter blending with standard pharmaceutical excipients. Moreover, themicro-particles can be milled via hammer or jet milling into about the 1to about the 10 microns range for use in inhalation applications or thelike.

Example 3 Wet Media Milling of a Superdisintegrant (CP: Crospovidone)

Wet media milling was done with the superdisintegrant alone. As-receivedCrospovidone (CP) was used in wet media milling. The particle sizestatistics of the as-received CP was D10-8.14, D50-20.97, and D90-45.70μm. The milling procedure was similar to that of Example 1 above. The CPloading was about 2% w/w.

The breakage dynamics of CP in the wet media mill is shown in FIG. 8,and an SEM image of the milled particles is shown in FIG. 9. The D90value of the 0 minute sample is about 41 μm (FIG. 8). It was reduced toabout 639 nm after about 4 hours milling in the wet media mill, as canbe seen in FIG. 8. Slight aggregation of the CP particles most likelyoccurred in the suspension because CP is a non-ionic cross-linkedpolymer and typically does not provide electrostatic repulsion. Theprimary particle size appears to be less than about 300 nm based on theSEM image (FIG. 9).

It is noted that one can add steric stabilizers like polymers tominimize the aggregation. Despite the aggregation, the feasibility ofwet milling the CP particles below about 300 nm, and subsequentpreparation of a CP suspension/formulation with greater than about 90%of the particles smaller than about 1000 nm has been shown.

Example 4 Wet Co-Grinding of a Superdisintegrant (SSG: Sodium StarchGlycolate) and a Poorly Water-Soluble Drug (FNB: Fenofibrate) in a WetStirred Media Mill

SSG and fenofibrate (poorly water soluble drug) were co-ground in a wetmedia mill. As received SSG particles were sieved and the particlessmaller than about 38 μm were used for the co-grinding experiments.

Similar to Example 2, the stability of the co-groundsuspensions/mixtures was ensured by using soluble biopolymerHydroxypropyl methyl cellulose (HPMC-E3). HPMC-E3 (about 1% w/w) wasfirst dissolved in de-ionized water (about 200 g). Fenofibrate (about10% w/w) was then added to the stabilizer solution and dispersed forabout 30 minutes with a shear mixer.

The milling procedure was the same as in Example 2 for CCS and FNBco-ground suspension production. Here, the SSG concentration was about3% (w/w). Samples were taken at about 0, 1 h, 2 h, and about 2.75 h tostudy the breakage dynamics during co-grinding. The results are shown inFIGS. 10-12.

FIG. 10 shows the milling dynamics of co-ground drug-superdisintegrant(FNB-SSG). The median size (D50) was reduced to about 184 nm aftermilling for about 2.75 hours, which was also confirmed by the SEM Image(FIG. 11). HPMC reduces the interfacial tension between FNB and water,and acts as a steric stabilizer. Similar to the CCS, SSG is ahydrophilic, anionic SDI which helps to stabilize the suspensionsfurther due to electrostatic repulsion.

To confirm the presence of nanoparticles of the superdisintegrant in theco-ground suspension sample, an EDX analysis of the dried sample wasperformed. The EDX analysis is based on the following elements: Na (fromSSG) and Cl (from FNB). The EDX map is shown in FIGS. 12A-C. Thepresence of nano-scale elemental domains originating from nano-milledSSG and FNB can be seen. The EDX analysis proves the presence ofnano-particulate SSG in the co-ground suspension. Again, asuperdisintegrant (SSG) can be co-ground to nanoparticles along with aBCS Class II (poorly water-soluble) drug and can produce stablenanoparticle suspensions/formulations.

Example 5 Wet Co-Grinding of a Superdisintegrant (CCS: CroscarmelloseSodium) and a Poorly Water-Soluble Drug (GF: Griseofulvin) in a WetStirred Media Mill; and Production of Nano-Composite Micro-Particles(NCMPs) Via Fluidized Bed Coating of the Wet-Milled Suspensions ontoPharmatose

The formulations of suspensions prepared are listed in Table 1. Allpercentages (%) refer to w/w with respect to deionized water (about 250g) when suspensions are considered.

TABLE 1 Formulation of the suspensions and drug (GF) content (withrelative standard deviation (RSD)) in nano-composite micro-particles(NCMPs). Drug content and Run GF HPC SDS Other additives RSD in NCMPs No(% w/w)^(a) (% w/w)^(a) (% w/w)^(a) (% w/w)^(a) (% w/w)^(a) 1 10 0 0 — 8.39 (12.91) 2 10 2.5 0 — 12.31 (5.77) 3 10 2.5 0 10 (Mannitol) 11.21(4.94) 4 10 2.5 0.5 — 13.61 (4.89) 5 10 2.5 0 0.9 (CCS, Unmilled^(b))11.91 (2.77) 6 10 2.5 0 0.9 (CCS, Milled^(c) 60 min) 12.11 (4.51) 7 102.5 0 0.9 (CCS, Milled^(c) 240 min) 12.82 (4.34) 8 10 2.5 0 0.9 (CCS,Milled^(c) + Unmilled)^(d) 12.78 (2.89) ^(a)% w/w is with respect to theweight of de-ionized water for suspensions. It also refers to the weightof GF with respect to the weight of NCMPs. ^(b)Unmilled CCS particlesare sieved CCS particles that were added to an already milledsuspension. ^(c)Milled CCS are CCS particles that were co-ground with GFparticles. ^(d)Contains about 0.45% milled CCS and about 0.45% un-milledCCS.

In Run 1, about 10% GF was dispersed in water for about 30 min using ashear mixer (Fisher Scientific Laboratory stirrer, Catalog no. 14-503,Pittsburgh, Pa., USA) before milling. For Runs 2-8, about 2.5%hydroxypropyl cellulose (HPC, neutral steric stabilizer) was dissolvedin water. About 0.5% sodium dodecyl sulfate (SDS, negatively chargedelectrostatic stabilizer) was added to the HPC solution only in Run 4.

About 10% griseofulvin (GF, poorly water-soluble drug) was then added tothe stabilizer solutions (Runs 2-8) and dispersed for about 30 min withthe shear mixer. Mannitol (Manni, sugar alcohol) and/or croscarmellosesodium (CCS, superdisintegrant) were used as additional dispersants inRuns 3 and 5-8, respectively. CCS was dry-sieved with a sieve shaker forabout 60 min before milling, and a sieve cut off (−550 mesh) was used inRuns 5-8 to minimize the clogging of the mill screen.

Mannitol and sieved CCS particles were added to the already milledsuspensions of about 10% GF/about 2.5% HPC in Runs 3 and 5,respectively, using a magnetic stirrer at a speed of about 600 rpm justbefore coating them onto Pharmatose®. Sieved CCS particles were alsoadded to the co-ground 10% GF/2.5% HPC/0.45% CCS suspension aftermilling in Run 8 (about 1:1 mass ratio of un-milled CCS to milled CCS).Mannitol has a high solubility in water (about 180 g/L) and dissolves inthe GF suspension, whereas CCS is generally insoluble and swells inwater.

Following the initial suspension/mixture preparation, about 275 to about283.5 g suspension was poured into the holding tank of a Netzsch mill(Microcer, Fine particle technology LLC, Exton, Pa., USA) and pumpedthrough the milling chamber at a flow rate of about 126 ml/min.

Zirconia beads with a median size of about 400 μm and a bulk volume ofabout 50 ml were used as the milling media in Runs 1-5. For Runs 6-8,about a 50/50 v/v mixture of about 400 μm and about 800 μm zirconiabeads was used to break the swollen CCS particles.

CCS powder was added gradually (˜0.4 g/min) to the suspension in theholding tank during the initial 6 min of milling because addition of allCCS powder instantaneously typically led to the clogging of the millscreen and shutdown of the process. When added gradually, the CCSparticles passed through the milling chamber and fractured whileswelling, which helped to minimize the fraction of large swollenparticles that can clog the mill. A 200 μm screen was used to retain thebeads in the milling chamber.

The suspensions were milled for about 80 min at a tip speed of about11.8 m/s (3200 rpm) for Runs 1-5, while milling was continued for about240 min and about 120 min for Runs 7 and 8, respectively. The millingtime was purposefully varied in Runs 6-8 to study the impact of particlesize of CCS on suspension stability and GF nanoparticle recovery fromNCMPs. The temperature inside the milling chamber was maintained atabout 32° C. with a chiller (Advantage Engineering, Inc., Greenwood,Ind., USA). Suspension samples were taken from the holding tank forparticle size analysis.

The particle size distribution of the milled suspensions was measured bylaser diffraction in Coulter LS13320 (Beckman Coulter, Miami, Fla.,USA). Suspensions samples were dispersed in about 15 ml of thestabilizer solution and added drop-wise until the polarization intensitydifferential scattering (PIDS) reached about 40%. The particle size ofthe GF suspensions was also measured at the end of the fluidized bedcoating run, e.g., about 30 hour after milling (about 24 h storage andabout 6 h of coating run, also termed as before re-dispersion).

The particle size statistics of as-received GF were D10: 3.9 μm, D50:16.0 μm and D90: 47.4 μm. Table 2 shows the particle size statistics forGF suspensions in Runs 1-8, after milling and before re-dispersion(about 30 h after milling). In Run 1, GF suspension with a median sizeof about 2.99 μm was produced. However, the SEM image of this suspensionsample (Run 1) shows the presence of primary GF nanoparticles (about150-600 nm range), even in the absence of stabilizers (FIG. 13).

These findings suggest that micron-sized GF particles were broken downdue to frequent bead-bead collisions creating colloidal particles andnanoparticles (defined as <1000 nm per prevalent pharmaceuticalengineering terminology), while the particles aggregated in the absenceof stabilizers due to the attractive inter-particle forces, such as vander Waals force.

Therefore, the GF suspension was not physically stable in the absence ofstabilizers. The median size was reduced to about 1.79 μm after millingin the presence of about 2.5% HPC as a stabilizer. HPC adsorbs on drugparticle surface during milling, imparting steric stability and reducingthe interfacial tension between GF and water. The particle size of Run 2suspension stored at about 8° C. did not change significantly 30 h aftermilling (before re-dispersion). However, the primary GF nanoparticleswere in an aggregated state due to the low polymer:drug mass ratio(about 1:4).

TABLE 2 Particle size of the GF and GF-CCS suspensions after milling andbefore redispersion test (30 h after milling). Particle size ofsuspensions after Particle size of suspensions Run Formulation milling(μm) before redispersion (μm) No (% w/w) D10 D50 D90 D10 D50 D90 1 Nostabilizers 0.26 ± 0.00 2.99 ± 0.02 6.13 ± 0.21 0.36 ± 0.01 4.79 ± 0.0210.65 ± 1.67  2 2.5 HPC 0.14 ± 0.01 1.79 ± 0.05 5.35 ± 0.54 0.13 ± 0.021.85 ± 0.10 4.24 ± 0.09 3 2.5 HPC, 10 Mannitol^(a) 0.12 ± 0.01 1.78 ±0.12 4.33 ± 1.12 0.13 ± 0.02 1.77 ± 0.09 4.52 ± 0.56 4 2.5 HPC, 0.5 SDS0.13 ± 0.00 0.16 ± 0.00 0.22 ± 0.00 0.12 ± 0.00 0.16 ± 0.00 0.21 ± 0.005 2.5 HPC, 0.9 CCS (Unmilled)^(a) 0.14 ± 0.02 1.85 ± 0.09 4.12 ± 0.190.28 ± 0.02 56.18 ± 2.69  89.67 ± 4.04  6 2.5 HPC, 0.9 CCS (Milled 60min) 0.14 ± 0.01 19.52 ± 3.91  67.57 ± 2.33  0.14 ± 0.00 21.79 ± 1.65 66.02 ± 5.01  7 2.5 HPC, 0.9 CCS (Mlled 240 min) 0.12 ± 0.00 0.16 ± 0.000.22 ± 0.00 0.12 ± 0.00 0.16 ± 0.00 0.22 ± 0.00 8 2.5 HPC, 0.9 CCS(Milled 120 min + 0.11 ± 0.02 0.16 ± 0.01 0.23 ± 0.02 0.09 ± 0.00 29.7 ±1.44 100.77 ± 2.02   Unmilled) ^(a)The after milling sizes refer to thesizes of GF milled with 2.5% HPC. Sieved CCS and Mannitol were added tothe milled suspensions before coating. The sizes of the suspensions arelisted under the particle size of suspensions before redispersion.

The addition of Mannitol (Run 3) did not alter the aggregation state ofthe about 10% GF/2.5% HPC suspension (Run 2). Mannitol was added as adispersant for the downstream processing to aid recovery of the GFnanoparticles. A stable GF nano-suspension was produced when acombination of about 2.5% HPC and about 0.5% SDS was used (Run 4). Themedian size was about 160 nm and did not change much after 30 h storage.The improved dispersion and stability can be explained by theinteractions between HPC and SDS via a complex formation resulting fromadsorption of SDS around the hydrophobic sites of HPC.

GF-CCS-HPC suspensions were prepared to study the impact of CCS onmilled GF particles. In Run 5, GF was milled with HPC as the stabilizerand sieved particles of CCS were added to this milled suspension viamagnetic stirring just before coating the final suspension ontoPharmatose® carrier particles.

The particle sizes of GF suspensions after milling in Runs 2, 3, and 5(about 10% GF/about 2.5% HPC) indicate that the milling results werefairly reproducible. The median size of Run 5 suspension increased toabout 56.18 μm after the addition of CCS before re-dispersion becausethe CCS particles swelled in water significantly. The dry particle sizeof CCS, as measured by Rodos/Helos laser diffraction system, was D10:12.90 μm, D50: 28.55 μm, and D90: 66.09 μm. The particle size increasedto D10:13.74 μm, D50: 63.68 μm and D90: 96.28 μm after about 3 hswelling in de-ionized water as measured by Coulter LS13320 with theliquid module.

The increase in particle size of GF/HPC suspension in Run 5 can thus beexplained by the fact that the volumetric ratio of swollen CCS particlesto GF particles is about 1.7:1 (the mass ratio of dry CCS to GF wasabout 1:11) and that the volume-based size distribution is governed moreby the larger particles than the smaller ones. Hence, the volume-basedsize distribution of the CCS-GF particles in the suspensions is largelydominated by the larger volume occupied by the swollen CCS particles inthe cumulative volume particle size distribution.

In Runs 6 and 7, suspensions containing about 10% GF/about 2.5% HPC wereco-ground with CCS particles for about 60 min and about 240 min,respectively, to produce suspensions containing differently sized CCSparticles. In Run 8, half of the CCS particles (about 0.45%) were milledwith about 10% GF/about 2.5% HPC, and the other half of CCS particleswas added after milling in order to have a mixture of un-milled andmilled CCS particles. The milling dynamics for the Run 7 suspension areshown in FIG. 14.

The particle size at about 8 min was measured after the gradual additionof CCS was completed in about 6 min. FIG. 14 shows that the median sizeof the about 2.5% HPC/about 0.9% CCS (Run 7) suspension reduced fromabout 47.93 μm to about 160 nm after about 240 min of milling. GFbreakage dynamics studies have suggested that GF particles were brokendown to a median size of <0.2 μm in about 32 min, which did not decreasesignificantly upon further milling (up to 64 min) under similar millingconditions and formulation (about 2.5% HPC, about 0.5% SDS) used here.

Since a dynamic equilibrium is known to occur within an hour for GFparticles, the gradual decrease in the particle size over a period ofabout 240 min (FIG. 14) can be attributed to slower breakage of the CCSparticles as compared with the GF particles. In general, breakage ofcross-linked polymers is challenging and wet media milling of CCS inthis study achieved the milling objective. CCS, being a cross-linkedbiopolymer, swells and absorbs water. Swelling induces softening andreduces the tensile strength, which may explain the significant extentof CCS breakage in this study albeit at a slower rate than the GFparticles.

FIG. 14 and Table 2 show that the particle size of the Run 7 suspensionmeasured after about 30 h (before re-dispersion) is substantially thesame as the particle size obtained after about 240 min of milling, whichsuggests that the Run 7 suspension was stable. Additional evidence forthe presence of GF and CCS nanoparticles in the range of about 50-300 nmin the Run 7 suspension is provided in FIG. 15. For Run 6, the millingof the about 10% GF/about 2.5% HPC/about 0.9% CCS suspension was stoppedafter about 60 min yielding a mixture of colloidal and larger swollenCCS particles along with GF nanoparticles and their aggregates (mediansize of about 19.52 μm).

In Run 8, the D50 and D90 particle sizes were about 0.16 μm and about0.23 μm in the presence of about 0.45% CCS after about 120 min milling,which was similar to that in Run 7 (containing about 0.9% CCS). Themedian particle size increased to about 29.7 μm before re-dispersion(see Table 2) due to the addition of the remaining 0.45% un-milled CCSparticles before the coating of the suspensions (about 30 h aftermilling).

The D50 and D90 values of the about 10% GF/about 2.5% HPC/about 0.9% CCSsuspension (Run 7, Table 2) were about 0.16 μm and about 0.22 μm afterabout 240 min milling, which are the same as those of the most stable GFsuspension, e.g., Run 4 (about 10% GF/about 2.5% HPC/about 0.5% SDS)suspension. Moreover, a comparison of the median sizes of milledsuspensions from Run 7 and Run 2 suggests that co-grinding of CCS withGF allowed a finer median size, e.g., about 0.23 μm vs. about 1.79 μm,(about 80 min milling time), respectively.

All these findings point to the enhanced stabilization of GF/HPCsuspension in the presence of milled CCS particles. CCS is an anionicsuperdisintegrant which ionizes into negatively charged croscarmelloseions and sodium cations at pH>2. It is known that colloidal particles(<1000 nm) can be stabilized by charged nanoparticles (about <100 nm)that provide a high electrical charge to the otherwise negligiblycharged colloidal particles. It is noted that unlike in the field ofcolloids, <1000 nm particles are called nanoparticles in the prevalentpharmaceutical terminology. It is also noted that electrostatic actionof the milled CCS particles on the stabilization of the GF/HPCsuspension is a potential mechanism for the improved stability.

Production of Nano-Composite Micro-Particles (“NCMPs”) Via Fluidized BedCoating of the Wet-Milled Suspensions onto Pharmatose

The milled suspensions, whose formulations are presented in Table 1,were stored for one day in a refrigerator at about 8° C. to minimizepotential growth of particles prior to their coating onto Pharmatose®carrier particles in a conventional bench-top fluidized bed processor(Mini-Glatt, Glatt Air, Ramsey, N.J., USA) with a top sprayconfiguration. About 100 g Pharmatose® powder was charged in the productbowl and fluidized at an inlet air pressure of about 0.4-0.5 bar.

After the powder was fluidized, the heater and suspension spray wereturned on. About a 200 g batch of suspension was pumped through aperistaltic pump (Masterflex L/S Cole-Parmer Company, USA) at a rate ofabout 0.60 ml/min for all runs. The suspensions were mixed with amagnetic stirrer throughout the coating run to prevent sedimentation ofthe particles. The suspensions were atomized through a bi-fluid nozzlewith about 0.3 mm nozzle diameter (diameter of the liquid tip) at anatomization air pressure of about 1 bar. The fluidization airtemperature was set at about 70° C. The coated powder continued tofluidize and dry for about 10 min after all the suspension was sprayedfor about 6 h. The coated powders were tested for drug assay, particlesize, and morphology and were subsequently used in the re-dispersion anddissolution tests.

The suspensions were coated onto Pharmatose® carrier particles in thefluidized bed processor. The particle size statistics of Pharmatose® asmeasured by Rodos is D10: 58 μm, D50: 116 μm and D90: 206 pan. Themedian particle size of Pharmatose® increased from about 116 μm to about120-150 μm due to coating and some agglomeration. The drug content ofthe nano-composite micro-particles (NCMPs) was determined by directassay and is given in Table 1.

In this method, about 100 mg of the dry NCMPs was dissolved in about 20ml of methanol (solubility of GF in methanol is about 30 mg/ml at about25° C.) and sonicated for about 30 min to ensure complete dissolution ofGF. Pharmatose® particles are generally insoluble in methanol, so theyremained suspended. After sonication, they were allowed to sediment, andan aliquot of about 100 μl was taken from the supernatant.

This aliquot was diluted to about 10 ml with methanol. The absorbance ofall the samples was measured at the wavelength of about 292 nm byUltraviolet (UV) spectroscopy in a UV Spectrophotometer (Agilent, SantaClara, Calif., USA). For each run, six samples from the NCMPs wereassayed and the mean drug content along with the relative standarddeviation (RSD) was calculated and reported in Table 1.

Run 1 shows the lowest GF content of about 8.39% (Table 1). In theabsence of HPC, the GF particles could not bind to the surface ofPharmatose® particles strongly and there was preferential loss of GFparticles due to attrition during coating. This sample also shows thehighest drug content variability. For Runs 2-8, the mean drug contentwas in the range of 11-14% with less than about 6% RSD for each run.FIG. 16A shows the SEM image of the Pharmatose® particles, and FIGS.16B-16D show the coated Pharmatose® particles (NCMPs) obtained viadrying of the GF/HPC/SDS suspension (Run 4).

From FIGS. 16A and 16B, the surface of as-received and coatedPharmatose® particles appears to be rough with external pores. The lackof smoothness in core Pharmatose® particles led to a non-homogenouscoating of the suspensions with a variable thickness of about 2-4 μm ina thin coating layer (FIG. 16D). The coated layer is composed of GFnanoparticles covered by HPC-SDS film and can be clearly seen on thesurface of the NCMP in FIG. 16C.

In Runs 2-8, HPC allowed formation of a rough drug-laden coating layer,which embeds and/or partially covers the GF particles on the surface ofPharmatose® particles, thus minimizing the drug loss and assayvariability (compare to Run 1 in Table 1). It is noted that bothwater-soluble (e.g., sugars like Pharmatose® here and sugar alcoholslike Mannitol) and insoluble excipients like microcrystalline cellulose,pre-gelatinized starch, etc. can be used as the core material during thefluidized bed coating.

The use of lactose (Pharmatose®) in the current example allows for athorough and fundamental understanding of GF nanoparticle release fromthe nano-composite micro-particles because Pharmatose® quickly dissolvesduring the re-dispersion or dissolution without having confoundingeffect on the measurement of GF and/or CCS particles. On the other hand,a soluble or insoluble excipient may be used as the core materialwithout loss of generality.

GF nanoparticle recovery during the re-dispersion of the NCMPs wasinvestigated by dispersing about 110-140 mg NCMPs (about 13 mg GFequivalent) prepared above in about 15 ml quiescent, de-ionized water ina vial at room temperature, and video imaging the dispersion. Theparticle size distribution (PSD) in the supernatant (liquid layer abovethe sediment) was measured by dynamic light scattering (Beckmann CoulterDelsa Nano C). Different NCMPs are labeled based on their dispersanttype/concentration in the respective precursor suspension. Table 3 andFIGS. 17A-D present the PSD statistics and images of the re-dispersions.

TABLE 3 PSD statistics of the supernatants measured via dynamic lightscattering (after about 5 min redispersion). For CCS, the abbreviationsindicate the following: M: milled, U: unmilled, NM: nanomilled for about240 min. Suspension Formulation d₁₀ d₅₀ d₉₀ (10% GF and variousdispersants) (nm) (nm) (nm) 2.5% HPC — — — 2.5% HPC, 10% Mannitol — — —2.5% HPC, 0.9% CCS 96 141 260 (NM) 2.5% HPC, 0.9% CCS 187 1417 8556 (UM)2.5% HPC, 0.9% CCS (M 124 182 333 60 min) 2.5% HPC, 0.5% SDS 92 129 200

NCMPs that do not contain CCS or SDS settled down fast, forming a clearsupernatant without significant number of particles (below thresholdconcentration in particle sizing), whereas those with SDS or CCS led toformation of a turbid, milky supernatant with nanoparticles and theirclusters. While the descending NCMPs led to induced fluid motion anddrag, the drag force could not overcome the gravity; white sedimentformed at the bottom of the vials and remained intact after about 30minutes.

Since nanoparticles and their clusters released were relatively smallcompared with the NCMPs (Table 3), they were suspended via Brownianmotion. It appears that full recovery of all nanoparticles did not occurduring re-dispersion in quiescent water. In these videos, it wasobserved that during their fall, NCMPs with SDS or CCS burst into acloud of extremely fine particles within about 30 s, which wereconfirmed to be mainly nanoparticles and their clusters via dynamiclight scattering (FIGS. 17C and 17D, Table 3).

Table 3 suggests that except for the NCMPs with un-milled CCS, thesupernatants were all colloidal after about 5 min (d₉₀<1 μm).Considering the extent/fineness of nanoparticles recovered, asuperdisintegrant (about 0.9%) appears to be far more effective than asugar alcohol (about 10%) at a much lower loading level, and it canpotentially replace or minimize use of the surfactant. Moreover, milledsuperdisintegrant particles can be more effective than un-milled CCSparticles for fast release of the GF nanoparticles from NCMPs inquiescent fluids.

Unlike HPC and mannitol which dissolve in water, CCS particles generallydo not dissolve, but swell extensively in water and co-exist with themilled GF particles upon re-dispersion of the NCMPs. Hence, in thepresence of CCS, a more accurate analysis of GF recovery duringre-dispersion should be performed via assaying of the supernatant. In aseparate re-dispersion test, about 1 g of the NCMPs was weighed anddispersed in about 30 ml water inside a small beaker for about 2 min viaa VWR (VOS 16) paddle stirrer operating at about 240 rpm.

Then, the re-dispersion sample was centrifuged (Becton Dickinson,Compact II centrifuge) for about 10 min at about 3200 rpm to separatethe nanoparticles from their aggregates and large, swollen CCSparticles. The supernatant obtained was assayed for GF to measure theamount of GF nanoparticles recovered in the re-dispersion test,minimizing any confounding effects due to the CCS particles. To thisend, a 40 μl supernatant sample was dissolved in about 10 ml of methanoland UV absorbance of the supernatant was measured at about 292 nm. Analiquot of the supernatant was also used to determine the particle sizedistribution via laser diffraction and to confirm the feasibility ofrecovering nanoparticles via centrifugation.

A qualitative assessment of GF nanoparticle recovery from NCMPs afterabout 2 min re-dispersion with paddle stirring was performed via SEMimaging (FIGS. 18A-F). The GF nanoparticles were not recovered fromNCMPs produced without SDS or CCS in Runs 1-3 as shown in FIGS. 18A-18C,which illustrate aggregates of GF nanoparticles.

Discrete GF nanoparticles were recovered from NCMPs containing HPC andSDS (Run 4, FIG. 18D), whereas discrete GF nanoparticles along with someaggregates were re-dispersed from NCMPs containing HPC with un-milledCCS (Run 5, FIG. 18E) and HPC with CCS milled for 60 min (Run 6, FIG.18F).

Overall, these SEM images suggest that GF nanoparticles were recoveredfrom NCMPs containing SDS or CCS. Extensive SEM imaging of Runs 5 and 6samples also showed some larger aggregates of GF particles, similar tothose observed in FIGS. 18B and 18C, along with the discrete GFnanoparticles. Thus, SEM imaging gives a qualitative and partial pictureof the re-dispersion phenomenon.

The particle size of NCMPs after about 2 min re-dispersion with paddlestirring was also measured. The particle sizes before and afterre-dispersion in Runs 5-8 refer to sizes of both the GF and CCSparticles because CCS is generally insoluble in water. Therefore,information about the GF nanoparticle recovery during the re-dispersiontest is partly concealed by the presence of the swollen CCS particles.To overcome this issue, the milled suspension sample was centrifuged toobtain supernatant containing nanoparticles, which was then assayed forGF. The particle sizes of the supernatants, which were obtained from theabout 2 min re-dispersion of the NCMPs followed by centrifugation, arereported in Table 4.

TABLE 4 Percent GF dissolved in 2 min during the USP II dissolutiontest, T80% of dissolution and percentage GF nanoparticles recovered andtheir size during the redispersion test. GF Supernatant nanoparticlesparticle size^(b) Run Suspension formulation used in fluidized bed GFT80%^(a) recovered^(b) D10, D50, D90 No coating dissolved (%) (min) (%)(μm) 1 10% GF, No stabilizers  2.9 ± 1.3 —  0.6 ± 0.4 NM^(c) 2 10% GF,2.5% HPC  3.7 ± 1.2 —  0.3 ± 0.2 NM^(c) 3 10% GF, 2.5% HPC, 10% Mannitol 4.4 ± 3.0 —  0.3 ± 0.2 NM^(c) 4 10% GF, 2.5% HPC, 0.5% SDS 77.0 ± 0.55.72 89.2 ± 6.9 0.123, 0.162, 0.219 5 10% GF, 2.5% HPC, 0.9% CCS(Unmilled) 33.9 ± 2.4 12.62 20.6 ± 0.9 0.110, 0.154, 0.228 6 10% GF,2.5% HPC, 0.9% CCS (Milled 60 min) 58.9 ± 1.2 7.55 41.8 ± 32  0.109,0.161, 0.239 7 10% GF, 2.5% HPC, 0.9% CCS (Milled 240 min) 27.2 ± 5.117.68 16.2 ± 1.9 0.119, 0.157, 0.215 8 10% GF, 2.5% HPC, 0.9% CCS(Milled 120 48.9 ± 2.4 7.85 27.8 ± 0.7 0.139, 0.159, 0.219 min +Unmilled) ^(a)T80%: time required for 80% of GF to dissolve.^(b)Redispersion: 2 min paddle stirring of the NCMPs in water followedby centrifugation and size analysis of the supernatant. ^(c)NM: NotMeasurable. Concentration of the particles was too low for properdetection during sizing in Coulter LS13320.

Table 4 shows that the supernatants of the NCMP formulations with CCS orSDS contained particles mostly <240 nm and that GF nanoparticles werenot recovered appreciably in Runs 1-3 in the absence of SDS or CCS inthe NCMPs. These findings corroborate the qualitative findings from SEMimages in FIGS. 18A-F. The supernatants obtained from Runs 1-3 wereclear solutions. The particle concentration was so low that it could notbe detected during particle size measurement by laser diffraction forthese runs.

However, particles <240 nm were recovered from Runs 4-8 containing SDSor CCS in the NCMPs. Runs 4-8 NCMPs exhibit enhanced GF nanoparticlerecovery as compared with Runs 1-3 NCMPs, confirming the successfulre-dispersion of the drug nanoparticles in the presence of either SDS orCCS in the coated layer of the NCMPs. However, the formulations in Runs4-8 cannot be differentiated based on the supernatant particle sizedistribution because GF nanoparticles in the D10-D90 range of about110-240 nm (Table 4) were recovered from all runs. On the other hand,these formulations can be rank-ordered based on the percentage GFnanoparticles recovered during the re-dispersion test (Table 4) and thepercentage of GF dissolved during the dissolution test (see below).

The GF nanoparticles in Run 1 formed hard aggregates on Pharmatose afterdrying, which led to only about 0.6% GF recovery from NCMPs (Table 4).Similarly, the soft aggregates of GF in Run 2 suspension with a mediansize of about 1.79 μm (Table 2) agglomerated and bound together by HPCduring drying.

HPC formed a film during drying and partially covered the GFnanoparticles. HPC reduces the interfacial tension between GF and water;however, it imparts poorer wettability compared to SDS and dissolvesslowly compared to Mannitol or SDS, which led to incomplete recovery ofthe GF nanoparticles from the GF-HPC agglomerates (clusters) thatemanated from the NCMPs during the re-dispersion.

Similarly, addition of Mannitol in Run 3 did not disperse the GF-HPCagglomerates. Mannitol dissolves from the coated layer of the NCMPscreating holes in the surface layer and helps to disperse the GF-HPCagglomerates; however, these agglomerates were not broken further by thedissolution of Mannitol. The inability of Mannitol to release GFnanoparticles completely points to a need for even higher Mannitol todrug ratio (greater than about 1:1). While higher Mannitol to drugratios may be used for improvement of nanoparticle recovery, a 1:1 ratiois already high and undesirable for a variety of reasons (e.g., highsugar content, diabetic patients, etc.). Hence, there is a need to findbetter dispersants that are effective at a smaller dispersant to drugratio.

GF nanoparticles were completely recovered from the NCMPs when thecombination of HPC and SDS was used (Run 4). SDS improved thewettability of the GF-HPC agglomerates, leading to their fastdisintegration into nanoparticles or their soft aggregates. Thesynergistic stabilization effect of HPC/SDS was explained by a complexformation, which resulted in the full recovery and stabilization of theGF nanoparticles. The wetting-dissolution mechanism imparted by HPC andMannitol (at high concentration about 1:1 with respect to GF) was notsufficient to break the GF-HPC clusters and to recover the GFnanoparticles completely if SDS was not used in the formulation (Runs 2and 3).

Therefore, a surfactant-free formulation with CCS as a dispersant at lowconcentration (GF:CCS ratio of about 1:0.09), in addition to HPC, wasused in Runs 5 (un-milled CCS), 6 (CCS milled for about 60 min), 7 (CCSmilled for about 240 min) and 8 (mixture of un-milled CCS and CCS milledfor about 120 min).

The incorporation of CCS in NCMPs promotes swelling-induced breakage ofthe drug layer of NCMPs and the GF-HPC clusters. CCS is a hydrophilic,water-insoluble superdisintegrant that can promote wettability of theNCMPs. It has a high hydration capacity (about 12.1 g water/g polymer).The swollen CCS particles, which appeared in the milled suspensions,shrunk during the fluidized bed coating process and swelled again incontact with water during the re-dispersion/dissolution of the NCMPs.Swelling of the CCS particles weakens the NCMP layer, causing its fasterbreakage and facilitating the recovery of the GF nanoparticles from theclusters emanating from the broken layer.

The percentage GF nanoparticles recovered during the re-dispersion test(Runs 5-8) varied depending on the formulation of the NCMPs in thefollowing order: HPC/GF/0.9% CCS milled for 60 min (Run 6)>HPC/GF/0.9%CCS with a 1:1 ratio of 120 min milled and un-milled CCS (Run8)>HPC/GF/0.9% CCS un-milled (Run 5)>HPC/GF/0.9% CCS milled 240 min (Run7) (Table 4). Runs 6 and 8 contain a mixture of colloidal and largermilled (Runs 6 and 8)/un-milled (Run 8) CCS particles.

The larger CCS particles are easily accessible by water due to theirlarger particle size in comparison to the milled CCS particles. Inaddition, they could exert a higher internal stress upon swelling,leading to more effective weakening of the layered structure of theNCMPs. Therefore, the un-milled CCS particles are expected to be moreeffective in breaking the surface layer of NCMPs and releasing theGF-HPC agglomerates quickly. Due to their smaller sizes, theagglomerates (about 1-5 μm) may not be broken down effectively by theun-milled CCS particles (D10-D90 size range of 12-66 μm), but by themilled (finer) CCS particles.

On the other hand, the finer CCS particles alone (Run 7) were not veryeffective in recovering GF nanoparticles because the coated layer didnot break quickly in the absence of larger CCS particles. The GFnanoparticle recovery in Runs 5 and 7 containing un-milled CCS andmilled (colloidal) CCS, respectively, was not very significant at about2 min: about 20% and about 16%. These results suggest that someoptimum/adjusted milling of CCS along with GF is necessary for improvedGF nanoparticle recovery. Indeed, about 60 min GF-CCS co-grinding (Run6), which caused the lowest extent of CCS particle breakage among allCCS milling cases, imparted the most favorable CCS size characteristics,which led to an improved GF recovery of about 41.8% in about 2 minutes.

A main reason for producing nanoparticles of poorly water-soluble drugs,such as GF, is to improve the dissolution rate of these drugs.Re-dispersion tests can help one to elucidate the drug nanoparticlerecovery from NCMPs and to explain the dissolution response. Drugdissolution from all NCMPs (Runs 1-8) and a physical mixture of Run 2(about 2.5% HPC/about 10% GF) NCMPs with sieved CCS particles inde-ionized water were measured and presented in FIG. 19 and Table 4.

Dissolution tests were carried out in a standard USP II apparatus withabout 50 rpm paddle speed. A sample of NCMPs (n=6) containing about 8.9mg GF were dissolved in about 1000 ml deionized water at about 37° C.,and samples taken from the vessel were syringe-filtered (0.1 μm filter)and assayed via UV spectroscopy. Unlike in the re-dispersion test, theuse of a large amount of water ensures substantially full solubilizationof the drug in this test.

The as-received GF particles had extremely slow dissolution in water,with only about 14% of GF being dissolved after about 60 min (result notshown in FIG. 19). The wet media milling of GF particles led toproduction of aggregates of GF nanoparticles and improved thedissolution rate (Run 1 NCMPs): about 36% in about 60 min (FIG. 19).However, the drug dissolution rate from Run 1 was still low due to poorrecovery of the GF nanoparticles from the NCMPs during the dissolution,as also observed in the re-dispersion tests.

The amount of GF dissolved in about 2 min increased slightly from about2.9% (Run 1) to about 3.7% and about 4.4% when about 2.5% HPC (Run 2)and about 2.5% HPC/10% Mannitol (Run 3) were used in the milledsuspensions, respectively. The percentage of GF dissolved from aphysical mixture of un-milled CCS particles (CCS outside layered NCMPs)with Run 2 (about 2.5% HPC/about 10% GF) NCMPs was similar to those ofRuns 2 and 3 NCMPs: about 5% GF dissolved in about 2 minutes.

As the dissolution progressed, the GF nanoparticles were graduallyrecovered over a period of time leading to about 47%, 64% and 52% ofdrug being dissolved from Runs 2, 3 and physical mixture of Run 2 withun-milled CCS particles (CCS outside layered NCMP structure),respectively, in about 60 minutes. Thus, it is concluded that CCSparticles outside the NCMP structure typically could not enhance thebreakage of the GF-HPC agglomerates and GF nanoparticlerecovery/dissolution much.

In Runs 5-8, CCS particles were present in the coated layer of the NCMPs(embedded during fluidized bed coating). The percentage GF dissolved inabout 2 min for Runs 5-8 ranged between about 27%-59%, which was about5-12 times greater than percentage GF dissolution from the physicalmixture, where CCS particles were present outside the layered NCMPstructure. This finding suggests that it is necessary to incorporate CCSparticles into the layered NCMPs for a fast breakage of the coatedlayer/GF clusters. The un-milled CCS particles were outside of thelayered NCMPs in the physical mixture; therefore, they could not exerttheir swelling-induced breakage action to release GF nanoparticles fromtheir clusters in the NCMPs.

Moreover, T80 (Table 4) in Runs 4-8 containing CCS or SDS is less thanabout 20 min, which implies a significant improvement in the GFdissolution rate. Dissolution of GF from NCMPs produced in Runs 1-3 andthe physical mixture did not reach 80% OF dissolution within about 60minutes. Therefore, the T80 values for these runs were not reported inTable 4. Also, the dissolution data at about 2 min were analyzed by apaired student t-test, which has been used in literature to comparedissolution profiles. P values of <0.05 were obtained for all runs,except Runs 5 (un-milled CCS) and 7 (milled CCS for about 240 min), thusindicating that the dissolution profiles were statistically differentfrom each other and that the different dispersants had significanteffects.

The comparison of the dissolution responses of Runs 5-8 NCMPs,containing a range of CCS particle sizes, suggests the need for anoptimal/adjusted CCS particle size for the fastest dissolution rate. Run6 NCMPs appear to have an optimum/adjusted balance between colloidal andlarger milled CCS particles resulting in about 59% dissolution of GF inabout 2 minutes. Run 8 NCMPs also consist of milled and un-milled CCSparticles and thus have a higher dissolution rate than NCMPs of Runs 5and 7.

Similar observations were made from the re-dispersion test. In fact, astatistically significant empirical correlation, in the form of a simplepower-law model (p<0.05 for both the model and its parameters,R²=0.979), was established between the percentage GF dissolved in about2 minutes during the dissolution test and percentage of the GFnanoparticles recovered during the 2 min re-dispersion test (FIG. 20)for all formulations. Hence, performing a re-dispersion test can be auseful tool for a rough prediction of the dissolution response and allowfor rank-ordering of different formulations and focusing on viableformulations during pharmaceutical development. Among all formulations,Run 4, which contains SDS, led to the fastest dissolution of GF. The GFsolubility is only slightly increased by SDS below the CMC.

Since the SDS concentration in the dissolution media was estimated to beabout 0.044%, which is much less than the CMC of SDS in water at roomtemperature (about 0.23%), the improved wettability with SDS andresultant improvement in GF nanoparticle recovery can explain the fasterdissolution. GF dissolution from Runs 6 and 8 containing milled CCS wasalso very fast. Overall, CCS and SDS were both found to enhance GFnanoparticle recovery and dissolution through thewetting-dissolution-breakage mechanisms, while CCS also imparts positiveeffects through the swelling-induced breakage of the NCMPs.

It is also possible to design sophisticated drug formulations with CCSand minimal amount of SDS (below CMC) in drug suspensions. Theseexperiments suggest that SDS can be partially or completely eliminatedfrom drug NCMP formulations without negatively affecting the drugsuspension stability and drug nanoparticle recovery during there-dispersion/dissolution. Hence, the use of colloidal/ultrafinesuperdisintegrant particles enable production of surfactant-free, drug(or any other pharmaceutical active agent) nanoparticle-laden,nano-composite micro-particles for fast and effective drug delivery.

Example 6 Incorporation of Co-Ground Superdisintegrant (SSG: SodiumStarch Glycolate) with a Poorly Water-Soluble Drug (GF: Griseofulvin) inNanocomposite Microparticles (NCMPs) Via Spray-Drying

The media milling conditions described in Example 2 were used forco-grinding SSG and GF in the presence of HPC (Hydroxpropyl cellulose,polymer). The formulation was about 10% (w/w) GF, about 2.5% HPC, andabout 1% SSG. The suspension was milled for about 79 minutes includingthe initial 12 minute addition of SSG.

Co-grinding of GF and SSG in the presence of HPC produced a nanoparticlesuspension with a median size of about 158 nm. Another suspensionwithout the superdisintegrant (SSG), e.g., a suspension with about 10%GF and about 2.5% HPC, was also produced under the same processingconditions, except that the latter suspension was milled for about 64minutes.

The nanoparticle suspensions prepared via wet media milling were driedusing a spray dryer (4M8-Trix, Procept, Zelzate, Belgium) to producenano-composite micro-particles. The spray flow setup was co-current. So,the hot air flow and spray of suspension was substantially in the samedirection.

The air flow rate and the air temperature was about 0.4 m³/min and about120° C., respectively. The cyclone separator pressure was maintained atabout 55-60 mbar. The suspensions were atomized through a bi-fluidnozzle with about 0.6 mm nozzle diameter (diameter of the liquid tip) atan atomization air pressure of about 2 bars.

The suspensions were pumped at a rate of about 1.3-1.5 g/min using apump (Make-it-EZ, Creates, Zelzate, Belgium). The suspension was mixedhomogenously with a magnetic stirrer throughout the spraying run toprevent sedimentation of the particles. The spray-dried powders werethen tested for particle size and used in the dissolution tests.

The dissolution procedure was similar to that of Example 5. The sampleswere taken out manually at about 1, 5, 10, 20, 30 and about 60 minutes.

FIG. 21 shows the dissolution rate improvement by the colloidal SSGparticles in the nano-composite micro-particles produced byspray-drying. About 88% of GF was dissolved in about 10 minutes from theGF/HPC/SSG nano-composite particles, whereas only about 47% GF wasdissolved from GF/HPC nano-composite particles.

SSG is an anionic superdisintegrant and hydrophilic in nature. SSGpromotes wettability and recovers GF nanoparticles by its swellingaction, which leads to increased dissolution rate. Furthermore, similarto colloidal CCS, colloidal SSG swells on absorption of water, and dueto the swelling mechanism it breaks the GF aggregates. Thus, SSG can beused to improve dissolution rate and bioavailability of poorlywater-soluble drugs such as GF without surfactants (e.g., substantiallysurfactant-free formulations) or with minimal amount of surfactants.Such results display the feasibility of surfactant-free drug formulationbased on wet-milled superdisintegrants.

As seen in certain embodiments, the surfactant-free wet milledsuspensions of superdisintegrants and active agents can be used assuspensions, or alternatively can be dried into compositemicro-particles via standard drying operations. These micro-particlescan be either directly filled into capsules, sachets, etc., or can becompressed into tablets or the like after blending with standardpharmaceutical excipients. In further embodiments, the micro-particlescan be further milled via hammer or jet milling into about the 1-10micron range for use in inhalation applications or the like. The presentdisclosure covers applications involving the production/fabrication,preparation, and/or use of wet-milled superdisintegrants in drugsuspensions and/or in drug nano-composite or composite micro-particles,which may ultimately be used in dosage forms such as tablets, capsules,powders, sachets, dry-powder inhalers, etc.

Certain embodiments of the present disclosure provide for asubstantially full recovery of active agents or nanoparticles. Thus, thepresent disclosure is more efficient than prior known methods (e.g.,methods utilizing sugar, sugar alcohols, water-soluble polymers).Further, as opposed to surfactants which cause irritation to sensorypulmonary epithelium, and may cause physical instability of drugsuspensions through Ostwald ripening and agglomeration, embodiments ofthe present disclosure do not have these drawbacks. Thus, embodiments ofthe present disclosure lead to substantial benefits.

Although the systems and methods of the present disclosure have beendescribed with reference to exemplary embodiments thereof, the presentdisclosure is not limited to such exemplary embodiments and/orimplementations. Rather, the systems and methods of the presentdisclosure are susceptible to many implementations and applications, aswill be readily apparent to persons skilled in the art from thedisclosure hereof. The present disclosure expressly encompasses suchmodifications, enhancements and/or variations of the disclosedembodiments. Since many changes could be made in the above constructionand many widely different embodiments of this disclosure could be madewithout departing from the scope thereof, it is intended that all mattercontained in the drawings and specification shall be interpreted asillustrative and not in a limiting sense. Additional modifications,changes, and substitutions are intended in the foregoing disclosure.Accordingly, it is appropriate that the appended claims be construedbroadly and in a manner consistent with the scope of the disclosure.

What is claimed is:
 1. A method for fabricating a formulationcomprising: providing superdisintegrant (SDI) particles; providingactive agent particles; co-wet-milling the SDI particles and the activeagent particles to form a mixture of wet-milled SDI particles and activeagent particles.
 2. The method of claim 1 further comprising the step ofdrying the mixture of wet-milled SDI particles and active agentparticles.
 3. The method of claim 2 further comprising the step ofincorporating the dried mixture into a solid dosage form.
 4. The methodof claim 2, wherein at least a portion of the dried mixture is coated onan excipient.
 5. The method of claim 2, wherein the drying step includesa drying technique selected from the group consisting of fluidized beddrying, spray drying, vacuum drying, freeze drying, spray freeze drying,oven drying, fluidized bed coating and fluidized bed granulation.
 6. Themethod of claim 1, wherein the mixture further includes a stabilizer. 7.The method of claim 6, wherein the stabilizer is selected from the groupconsisting of soluble polymers, hydroxpropylmethyl cellulose,hydroxpropyl cellulose and polyvinylpyrrolidone and combinationsthereof.
 8. The method of claim 1, wherein the mixture of wet-milled SDIparticles and active agent particles is a suspension of SDI particlesand active agent particles.
 9. The method of claim 8, wherein thesuspension contains colloidal and ultrafine SDI particles, and colloidalparticles and nanoparticles of active agents.
 10. The method of claim 9further comprising the step of drying the suspension to form anano-composite of SDI and active agent micro-particles.
 11. The methodof claim 1, wherein the active agent particles include particlesselected from the group consisting of pharmaceutical active agents,poorly water soluble drugs, diagnostic agents, peptides, proteins,biologic agents and combinations thereof.
 12. The method of claim 1,wherein the SDI particles and active agent particles are co-wet-milledin a wet media mill with milling media; and wherein the milling mediahas a particle size of about 25 μm to about 4 mm.
 13. The method ofclaim 1, wherein the SDI particles and active agent particles areco-wet-milled in size reduction equipment selected from the groupconsisting of wet stirred media mill, wet ball mill, planetary mill, andmilling equipment utilizing a high pressure homogenizer.
 14. The methodof claim 1, wherein the SDI particles include particles selected fromthe group consisting of croscarmellose sodium particles, sodium starchglycolate particles, crosslinked polyvinyl pyrrolidone particles,anionic SDI particles and neutral SDI particles.
 15. The method of claim1, wherein the wet-milled SDI particles have a particle size of lessthan about 5 microns.
 16. The method of claim 1, wherein the mixture ofwet-milled SDI particles and active agent particles is a suspension ofSDI particles and active agent particles; and further comprising thestep of coating and drying the suspension onto an excipient via afluidized bed processor to form a nano-composite of SDI and active agentparticles on at least a portion of the excipient.
 17. The method ofclaim 1, wherein prior to wet-milling the SDI particles and active agentparticles, the SDI particles are provided in a suspension at aweight/weight (w/w) % of from about 0.50 w/w % to about 5.0 w/w % withrespect to the weight of the water or suspension; and wherein the activeagent particles are provided in the suspension at a weight/weight (w/w)% of from about 5.0 w/w % to about 40.0 w/w % with respect to the weightof the water or suspension.
 18. The method of claim 1, wherein themixture of wet-milled SDI particles and active agent particles is asuspension of SDI particles and active agent particles; and furthercomprising the step of drying the suspension via a spray dryer to form anano-composite of SDI and active agent particles.
 19. A method forfabricating colloidal and ultrafine superdisintegrant (SDI) particlescomprising: providing SDI particles; wet-milling the SDI particles in awet media mill to form colloidal and ultrafine SDI particles; whereinthe wet-milled SDI particles have a particle size of less than about 5microns.
 20. The method of claim 19, wherein the wet-milled SDImicro-particles have a particle size of about 50 nm to about 1000 nm.21. The method of claim 19 further comprising the step of adding thewet-milled SDI micro-particles to active agent particles.
 22. The methodof claim 21, wherein the wet-milled SDI micro-particles are mixed withthe active agent particles to form a suspension.
 23. The method of claim21, wherein at least a portion of the active agent particles are inpowder form.
 24. The method of claim 19, wherein prior to wet-millingthe SDI particles, the SDI particles are provided in a suspension at aweight/weight (w/w) % of from about 0.50 w/w % to about 5.0 w/w % withrespect to the weight of the water or suspension.
 25. The method ofclaim 22 further comprising the steps of: (i) drying the suspension toform a composite of SDI and active agent particles, and (ii)incorporating the dried composite into a solid dosage form.
 26. Themethod of claim 19, wherein the wet media mill includes milling media,the milling media having a particle size of about 25 μm to about 4 mm.27. The method of claim 22 further comprising the step of coating anddrying the suspension onto an excipient via a fluidized bed processor toform a composite of SDI and active agent particles on at least a portionof the excipient.
 28. A method for fabricating a formulation comprising:providing superdisintegrant (SDI) particles and active agent particlesin a suspension, the SDI particles provided in the suspension at aweight/weight (w/w) % of from about 0.50 w/w % to about 5.0 w/w % withrespect to the weight of the water or suspension; co-wet-milling the SDIparticles and the active agent particles in a wet media mill to form anano-particle suspension of wet-milled SDI particles and active agentparticles; drying the nano-particle suspension to form a nano-compositeof SDI and active agent micro-particles; incorporating the driednano-composite into a solid dosage form; wherein the wet-milled SDIparticles have a particle size of less than about 5 microns.